Docetaxel Promising as Treatment for NSCLC

BOCA RATON, Fla--Docetaxel (Taxotere) is showing promising single-agentactivity in non-small-cell lung cancer (NSCLC), said James Rigas, MD, director,Thoracic Oncology Program, Norris Cotton Cancer Center, Dart-mouth-HitchcockMedical Center (Lebanon, NH).

In the United States, the drug has been approved for use in anthracycline-resistantbreast cancer, and in other parts of the world, it is available for usein NSCLC. From the US trial data, Dr. Rigas thinks that its use in thetreatment of NSCLC seems warranted.

"We started trials with Taxotere in NSCLC in 1992," Dr. Rigassaid at the annual meeting of the Network for Communication and OncologyResearch. His talk focused on the phase II trials, which took place inEurope (EORTC) and the United States (Memorial Sloan-Kettering, M.D. AndersonCancer Center, and the University of Texas Health Sciences Center, SanAntonio).

Of the 379 patients enrolled, 291 were chemotherapy-naïve and 88had failed prior platinum-based chemotherapy regimens. The chemotherapy-naïvepatients took part in four single-agent phase II trials (n = 160) and threephase I/II cisplatin (Platinol) combination trials (n = 131). The platinum-resistantpatients were enrolled in two single-agent phase II trials.

The criteria for the chemotherapy-naïve patient population weremetastatic or locally advanced lung cancer, a contraindication to combinedmodality therapy, no prior cytotoxicity to chemotherapy, and no radiationwithin three weeks of starting the trial.

In the single-agent phase II trials, docetaxel was given every 21 daysat a dose of 100 mg/m² infused over one hour. The cisplatin/docetaxelcombination trials established a standard dosing regimen, given every 21days, of docetaxel, 75 mg/m² infused over one hour with cisplatin,75 mg/m².

Antitumor activity was assessed at three weeks by physical examinationand x-ray, and at six weeks by CT scan. A follow-up CT scan was given withinfour to six weeks to confirm the response, Dr. Rigas said.

The response rate in the intent-to-treat analysis for the single-agentphase II trials was 27% (95% confidence interval: 20% to 34%). "Thiswas not a randomized trial," Dr. Rigas commented, "but ratherthe pooled result of data on all 160 patients treated."

The median survival was nine months with an estimated one-year survivalrate of 34%.

The 88 patients who had previously failed a platinum-based regimen showeda response rate of 17% (95% confidence interval: 10% to 27%). The mediansurvival rate was nine months, and one-year survival, 38%.

The 131 patients treated in the phase I/II combination trials had aresponse rate of 38%, median survival of 10 months, and one-year survivalof 40%.

Side Effects

Early into the phase II trials, the researchers began to see that peripheraledema, primarily in the ankles, was a cumulative side effect of the compound.Dexamethasone premedication was shown to lessen the frequency and severityof fluid retention, infusion-related reactions, and rash.

"The use of corticosteroids has even helped the infusion reactions,"Dr. Rigas said. "And if there is an infusion reaction, the infusioncan be stopped and restarted in 20 or 30 minutes."

Neutropenia was a significant side effect, with 54% of patients havinggrade 4 leukopenia and 7.3%, febrile neutropenia. About 3% had grade 4leukopenia lasting more than seven days.

"A retrospective analysis of multiple variables that may have contributedto the efficacy and toxicity of Taxotere in the trials was possible,"Dr. Rigas said, "because the sponsor of the studies, Rhône-PoulencRorer, had the insight to make a population pharmacokinetic model for Taxotere."

Model Predicts Neutropenia Risk

This model, based on the blood samples collected during most of thephase II trials, included both the breast cancer and lung cancer trials.From this database, Dr. Rigas said, a combination of liver function abnormalitieswas identified that predicts which patients are most likely to developneutropenia and febrile neutropenia.

"This population pharmacokinetic database is the largest studyfor any oncologic drug developed that I know about," Dr. Rigas said.

He noted that other lung cancer trials are in progress using docetaxelin combination with different agents, including carboplatin (Paraplatin),cisplatin, vinorelbine (Navelbine), gemcitabine (Gemzar), and irinotecan(Camptosar), as well as thoracic radiation.

Trials of docetaxel as primary chemotherapy for stage III NSCLC arewarranted based on its success in early studies, Dr. Rigas believes.